1. Field of the Invention
This invention relates broadly to articles of manufacture for administration of topical medicaments to human skin (as opposed to systemically active drugs) in a controlled release manner. The articles are moisture-vapor-permeable and oxygen-permeable but are impermeable to water in the liquid phase. The articles consist essentially of:
(i) a polymeric backing which in many instances is elastomeric.sup.* ; FNT .sup.* The terms "elastomeric" and "elastomer" are herein intended to cover polymers having reasonable degrees of elasticity; however, such "elastomer polymers" are to be expected to have finite yields. Thus, for example, an "elastomer" is a polymer herein intended to have an elongation greater than 150% under applied stress. PA0 (ii) adhering to one surface of the polymeric backing, a medication reservoir which is a mixture of a polyvinyl chloride polymer, a polymeric plasticizer and a topical medicament. Adhering to the medication reservoir on a surface opposite to backing layer is a pressure sensitive adhesive. Examples of topical medicaments useful in the practice of our invention are tolnaftate, chlorhexidine, chlorhexidine esters, chlorhexidine salts, hydrocortisone, benzalkonium salts, benzethonium salts and polyvinyl pyrrolidone-iodine complexes. PA0 A drug delivery device for the controlled, oral administration of water-soluble prednisolone is prepared as follows: first, a plurality of drug reservoirs comprising porous, discrete particles of polymerized poly(vinyl chloride) of about 100 microns diameter are prepared by mixing 100 g of suspension grade poly(vinyl chloride) resin with 50 g of octyl diphenyl phosphate and 10 g of prednisolone disodium phosphate at room temperature into a sticky, wet mass. Next, the temperature of the mixture is raised to 80.degree. C. for about 3 to 7 minutes, while stirring, to form dry, free flowing, discrete drug reservoirs. The reservoirs are uniformly dispersed through a matrix by mixing 50 g of reservoirs containing the prednisolone with 140 g of polydimethylsiloxane, 10 g of silicone oil, and 0.5 g of stannous octoate. After mixing the ingredients, the mixture is charged into pill molds and allowed to cure for 30 minutes. Oral administration of the resulting device yields a controlled essentially constant rate of release of prednisolone phosphate to the gastrointenstinal tract to give a more uniform blood level of prenisolone over a longer period of time than is achieved when prednisolone alcohol is administered by standard prior art pills. PA0 (i) a polymeric (and in many instances "elastomeric") backing material lamina; PA0 (ii) adhering to one side of the polymeric backing material lamina, a medication reservoir lamina which is a mixture of a polyvinyl chloride resin containing a polymeric plasticizer and a topical medicament compatible with the polyvinyl chloride resin and adhering to the other side of the plasticized polyvinyl chloride resin layer a pressure-sensitive adhesive unaffected by liquid water.
2. The Prior Art
A relatively new concept in wound management is the use of thin transparent elastomeric film dressings as opposed to conventional gauze dressings. Such elastomeric film dressings are known in the prior art and consist usually of a polyurethane film with a laminated pressure-sensitive adhesive for adhesion to the skin. The elastomeric film dressings of the prior art have high moisture vapor and oxygen permeability which properties are believed to be responsible for faster wound healing (of the order of 40% faster than when using conventional gauze dressings). The polyurethane film dressings of the prior art act as barriers to bacteria and liquid water, thus minimizing the risk of infection. Subsequent to 1980, the concept of the elastomeric film dressing has gained acceptance in hospital practice at a progressively rapid rate. The single most use of the polyurethane elastomeric film dressing is as a device for securement of peripheral and central intravenous catheters. Other applications are as a wound dressing for decubitus ulcers, autograft donor sites and partial thickness skin loss wounds. Existing commercial products of the prior art include OP-SITE.RTM. produced by T. J. Smith and Nephew Limited of Kingston-Upon-Hull, England, TEGADERM.RTM. produced by the Minnesota Mining and Manufacturing Company of St. Paul, Minn., BIOCLUSIVE.RTM. manufactured by the Johnson & Johnson Company of New Brunswick, N.J., POLYSKIN.RTM. manufactured by the Kendall Company, Division of Colgate Palmolive Company and ENSURE-IT.RTM. manufactured by the Deseret Medical Company, Division of Becton Dickinson of Franklin Lakes, N.J.
In the article "A Bandage That Acts Like Skin" in BUSINESS WEEK of Oct. 5, 1981, at page 381, it is disclosed that hospital studies indicate that OP-SITE.RTM., a transparent polyurethane film cuts healing time by up to 40% compared with the usual gauze bandage.
U.S. Pat. No. 3,645,835 issued on Feb. 29, 1972 and reissued as Re. U.S. Pat. Nos. 31,886 on May 14, 1985 and 31,887 on May 14, 1985 (assigned to T. J. Smith & Nephew Limited) discloses a moisture-vapor-permeable pressure-sensitive adhesive material for use on animal skin comprising a backing material and a pressure-sensitive adhesive on at least substantially the whole of the body adhering portion of at least one surface of the backing material, both the backing material and the adhesive being moisture-vapor-permeable and unaffected by water; with at least one of the backing material and/or the adhesive comprising a synthetic polymer and being continuous and non-permeable to liquid water, the adhesive material have a moisture-vapor-permeability of at least 300 grams/square meter/24 hours/40.degree. C./80% relative humidity. It is indicated therein that a preferred backing material is a polyurethane film.
U.S. Pat. No. 4,596,738 issued on Jun. 24, 1986 assigned to Smith and Nephew Associated Companies p.l.c. discloses a moisture vapor transmitting elastomeric film which comprises a blend of incompatible polymers and contains voids characterized in that the blend comprises a continuous matrix of ethylene vinyl acetate within which the incompatible polymer forms a discrete particulate phase matrix and further discloses that the film is liquid water impermeable and has a moisture-vapor transmission rate of at least 500 g/m.sup.2 /24 hours at 37.degree. C. at 100% to 20% relative humidity difference.
European Patent Application 174 803 filed on Sep. 5, 1985 assigned to Smith and Nephew Associated Companies p.l.c. discloses a bacteria proof adhesive wound dressing having a moisture vapor transmission rate of greater than 300 g/m.sup.2 /24 hours at 37.degree. C. at 100% to 10% relative humidity difference and which comprises a film which is coated on one face by an adhesive layer and has bonded to its other face a layer of foam. It is further disclosed therein that the foam is preferably a reticulated polyurethane foam from 0.5 to 2 mm thick.
U.S. Pat. No. 4,310,509 issued on Jan. 12, 1982 assigned to Minnesota Mining and Manufacturing Company of St. Paul, Minn. discloses a pressure-sensitive adhesive having homogeneously dispersed therein a broad-spectrum antimicrobial agent. It is further disclosed that when the composition is placed in contact with the skin, it uniformly and controllably releases the broad-spectrum antimicrobial agent with substantially unaltered broad-spectrum antimicrobial activity. Exemplified is the polyvinyl pyrrolidone iodine complex. Similarly, U.S. Pat. No. 4,323,557 discloses the polyvinyl pyrrolidone-iodine complex in the pressure-sensitive adhesive.
U.S. Pat. No. 4,542,012 issued on Sep. 17, 1985 discloses a dermatologically acceptable film-forming composition comprising a film-forming polymer and as a broad spectrum antimicrobial agent, iodine which forms a complex with the film-forming polymer. It is further disclosed therein that the compositions when applied to skin from a fugitive solvent form a substantially water-insoluble tack-free flexible film which adheres to the skin, releases the antimicrobial agent when the film is in contact with the skin and exhibits an elongation of at least about 150%.
German Offenlegungsschrift 3520 011 and United Kingdom Application 2,160,420 assigned to Yissum Research and Development Company disclose a composition for topical application for the gradual release of iodine comprising a hydrophilic polyurethane as a carrier of the iodine. It is further disclosed that the compositions release iodine in a gradual and predetermined manner over a prolonged time. It is further disclosed therein that the physical properties of the carrier and the germicidal properties of the iodine result in the prevention or control of infections, in exudate absorption, in crust removal and in rapid healing of sores because of the iodine release when the composition is applied to sores, wounds, burns and skin damage.
PCT Patent Application 86/00536 assigned to Avery International Corporation discloses a bandage for the transdermal or topical administration of a drug over an extended period of time comprising an impermeable backing sheet, a solid drug pellet on the backing sheet and a layer of contact adhesive covering the pellet and backing sheet. Control over the rate of dissolution of the solid drug can be achieved by varying the type of web fabric, the type of adhesive and the thickness of the adhesive.
U.S. Patent No. 4,576,818 issued on Mar. 18, 1986 provides iodophors which exhibit effective degerming of skin, mucous membranes of animals and surfaces of inanimate objects which provide broad spectrum microbicidal action. The iodophors of 4,576,818 are complexes of iodine with polydextrose or with the polymer resulting from the copolymerization of sucrose and epichlorohydrin.
European Patent Application 184 465 filed on Dec. 6, 1985, assigned to Warner-Lambert Company discloses an antithrombogenic thermoplastic polyurethane product comprising a substrate and at least one layer of a polyurethane alloy complex comprising a thermoplastic polyurethane and completely dispersed therein a preformed complex of an antithrombogenic material and/or an antibiotic agent ionically bonded with a quaternary ammonium compound.
U.S. Pat. No. 3,598,122 assigned to the Alza Corporation and issued on Aug. 10, 1971 discloses a bandage for use in the continuous administration of systemically active drug by absorption through the skin comprising a backing member having on one surface thereof a reservoir containing a systemically active drug. The reservoir has a wall distant from the backing member and permeable to the passage of the drug. The pressure-sensitive adhesive layer also permeable to the passage of the drug is carried by the reservoir.
U.S. Pat. No. 3,734,097 issued on May 22, 1973 discloses an adhesive laminate tape for the topical administration of a controlled therapeutically effective quantity of drug which may be selected from the group consisting of antineoplastic agents, folic acid antagonists and antimitotic agents for the treatment of skin lesions comprising a backing member bearing a pressure-sensitive adhesive, the adhesive having distributed therein a means for metering the flow of a therapeutically effective amount of the drug to the lesions over a prolonged period of time.
European Published Application 177 329 filed on Oct. 1, 1985 discloses a device for transdermal administration of nitroglycerin comprising a solid vinyl plastisol layer for contacting the patient's skin, the layer containing from about 40-70% of an emulsion polymerized polyvinyl chloride resin, from about 25-45% plasticizer and from about 5-20% nitroglycerin, and a backing layer opposite the skin-contacting surface as a barrier to the release of nitroglycerin.
Canadian Patent 930,668 discloses a bandage for administering drugs comprised of a backing member, a pressure sensitive adhesive, and at least one reservoir disposed between the backing member and pressure sensitive adhesive. The reservoir is comprised of a systemically active drug formulation confined within a wall member, the wall member being formed from a drug release rate controlling material. The reservoir can be in the form of discrete microcapsules or distinct reservoir compartments or layers. The reservoir can also be in the form of walled containers having one or more interior drug-containing chambers, as well as solid matrixes having a systemically active drug distributed therethrough. The Canadian patent discloses a wide variety of materials which can be used to form the reservoir. Among the materials mentioned are silicone rubbers, hydrophilic polymers of monoesters of an olefinic acid, polyvinylalcohol, polyvinylacetate, plasticized polyvinylchloride, plasticized nylon, collagen, modified collagen, getain and waxes such as polyethylene wax, oxidized polyethylene wax, hydrogenated castor oil and the like, with the silicone rubbers being preferred. The Canadian patent does not contain any examples showing the use of plasticized polyvinyl chloride, and does not show the use of a PVC plastisol.
Similarly, Zaffaroni, U.S. Pat. No. 3,921,636 issued on Nov. 25, 1975 discloses a drug delivery device for administering a drug at a controlled rate for a prolonged period of time comprising a plurality of reservoirs containing drug distributed through a matrix. The reservoirs and the matrix are formed of materials permeable to passage of the drug. The rate of drug permeation from the reservoir is lower than the rate of permeation through the matrix so that release from the reservoir is the drug release rate controlling step. Thus, Example 6, at column 15, lines 5-30 of U.S. Pat. No. 3,921,636 relates to a polyvinyl chloride resin containing plasticizer and prednisolone disodium phosphate thusly:
Furthermore, as is well known, polyvinyl chloride (PVC) is never used alone, but is always mixed with other ingredients before being processed. Polyvinyl chloride appeared initially to be an unpromising resin because of its thermal instability and high rigidity. PVC, however, was then discovered to form a rubber-like material when dissolved hot in high boiling solvents known as plasticizers and cooled to room temperature. PVC is now available in a number of different physical forms and types, and its manufacture depends on the form desired. Thus, PVC is available as a vinyl latex, a dispersion resin, or a general purpose resin. PVC latexes are true colloidal dispersions of submicrometer particles in water, stabilized by a surfactant system, and need plasticizers in order to form a continuous film. The PVC in vinyl latex is manufactured by emulsion polymerization.
Dispersion resins are produced by emulsion polymerization and are mixed with plasticizers to form a colloidal dispersion. Such dispersions are known as plastisols and are easily handled and readily pourable. When heated to a temperature of about 148.degree. to 177.degree. C., the plastisol is transformed to a homogeneous melt which, upon cooling to below 50.degree. C., results in a tough flexible product. The PVC resins made by emulsion polymerization are hard spheres of particle size between about 0.05 and 20 microns, such as between 1 and 20 microns. They do not have the ability to absorb plasticizers. Therefore, a mixture containing, for example, 30% plasticizer and 70 PVC resin, produces a flowable liquid, known as plastisol.
General purpose PVC resins are made by mass and suspension polymerization process, and comprise the largest amount of PVC resins produced, such as at least 80% of all PVC resins, and are used chiefly to make so-called 100% vinyl products by a variety of molding and extrusion techniques. Resins intended for flexible applications should have good uptake of plasticizer in a dry blending operation and contain more than 25% of a plasticizer system. PVC compounds that contain less than 25% plasticizers are referred to as semirigid compounds. The PVC resins manufactured by suspension and bulk polymerization are 50 to 200, such as 100 to 150 microns in diameter, and are like sponges. They are capable of absorbing large amounts of plasticizers, so that even a 50% plasticizer, 50% PVC resin composition would result in a non-flowing, solid material.